IL-1β Regulates the Balance Between Inflammation and Immunity in the Tumor Microenvironment

Interleukin-1β (IL-1β) is abandant in the tumor microenvironment, where it can have both pro- and anti-tumorigenic activities. Here, we studied these activities of IL-1β during early tumor progression using a model of orthotopically introduced 4T1 breast cancer cells. Whereas in wild-type (WT) mice, there is tumor progression and spontaneous metastasis, in IL-1β deficient mice, tumors begin to grow but subsequently regress. This change is due to alterations in recruitment and differentiation of inflammatory monocytes in tumor sites. In WT mice, tumor-associated macrophages (TAMs) heavily infiltrate tumors, but in IL-1β deficient mice, low levels of CCL2, hamper recruitment of monocytes and together with low levels of CSF-1 inhibit their differentiation into TAMs. The low levels of TAMs in IL-1β deficient mice results in a relatively high percentage of monocyte-derived dendritic cells in tumor sites. In WT mice, IL-10 secretion from TAMs is dominant and induces immunosuppression and tumor progression; in contrast in IL-1β deficient mice, IL-12 secretion by DCs prevails and supports anti-tumor immunity. The anti-tumor immunity includes activated CD8⁺ lymphocytes, expressing IFNg, TNFa and Granzyme B, which infiltrate into tumors in IL-1β deficient mice and induce regression. WT mice with 4T1 tumors were treated with either anti-IL-1β or anti-PD-1 antibodies, which resulted in partial growth inhibition. However, treating mice first with anti-IL-1β antibodies followed by anti-PD-1 antibodies, completely abrogated tumor progression. These data define microenvironment-derived IL-1β as a master cytokine that determines patterns of tumor progression and they also emphasize the status of anti-tumor cell immunity as a major factor in invasiveness.